This application seeks to advance the therapeutic development of a new class of histone deacetylase (HDAC) inhibitors through a performance-screening paradigm, consisting of cell culture, Drosophila and mouse models of Huntington's disease (HD). Clinical candidate testing will include full pre-clinical assessment leading to submission of an Investigational New Drug application to the US FDA. We have identified a novel HDAC inhibitor chemical scaffold (pimelic diphenylamides) that is efficacious in reversing disease phenotype in the R6/2 mouse model for HD, while showing no acute or chronic toxic effects. We have on hand a library of derivatives of this molecule, and in this proposal, we seek to (1) perform a structure-activity relationship screen to identify HDAC inhibitors that reverse gene expression changes and alter histone acetylation in polyQ containing striatal cells as a cellular model for HD; screen our HDAC inhibitor library in a Drosophila model for polyQ expansion to determine in vivo potency in reversing neurodegeneration, and to determine the relationship between HDAC enzyme specificity and in vivo activity; to characterize the in vivo pharmacology properties of HD-active compounds in rodents. (2) Test the top candidate molecules identified in cell and Drosophila screens in R6/2 HD transgenic mice; (3) Create a HD-targeted library of compounds to optimize safety, pharmacology and potency in anticipation of developing long-term oral dose treatments. Compounds will be assessed for HDAC inhibition activity and potency in the cell-based and Drosophila models and in vivo pharmacology; test the top 5 compounds identified above in the R6/2 mouse model, and test the two best compounds in the YAC128 mouse model of HD, which expresses full-length mutant huntingtin protein to reduce potential for animal model bias in surrogate efficacy. (4) Pilot toxicity and safety profiles will be determined with the top two compounds in rodents and non-rodents to help choose the final clinical candidate; methods for production of clinical grade drug product will be developed; and, an IND enabling package of pharmacology, safety and toxicology to guide human testing will be completed. PUBLIC HEALTH RELEVANCE: We recently identified a class of small molecules called histone deacetylase (HDAC) inhibitors that prevent neurodegeneration in a mouse model for Huntington's disease (HD), without toxicity problems that have been encountered with other types of HDAC inhibitors in other studies. In this application we seek to explore these HDAC inhibitors as potential therapeutics for HD.